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Thromb Haemost 2022; 122(10): 1767-1778
DOI: 10.1055/s-0042-1749328
Stroke, Systemic or Venous Thromboembolism

DNA Methylation and Ischemic Stroke Risk: An Epigenome-Wide Association Study

Natalia Cullell   *
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
2   Department of Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain
3   Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
,
Carolina Soriano-Tárraga   *
4   Neurovascular Research Group, Department of Neurology, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
5   Department of Psychiatry, NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, United States
,
Cristina Gallego-Fábrega
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
,
Jara Cárcel-Márquez
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
,
Nuria P. Torres-Águila
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
6   Evolutionary Developmental Genomics Research Group, The Scottish Oceans Institute, University of St Andrews, St Andrews, United Kingdom
,
Elena Muiño
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
,
Miquel Lledós
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
,
Laia Llucià-Carol
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
7   Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
,
Manel Esteller
8   Josep Carreras Leukaemia Research Institute, Barcelona, Spain
9   Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
10   Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
11   Centro de Investigación Biomédica en Red Cancer, Barcelona, Spain
,
Manuel Castro de Moura
8   Josep Carreras Leukaemia Research Institute, Barcelona, Spain
,
Joan Montaner
12   Department of Neurology, Hospital Universitario Virgen Macarena, Institute of Biomedicine of Seville/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain
,
Alba Fernández-Sanlés
13   Cardiovascular Epidemiology and Genetics Research Group, IMIM, Barcelona, Spain
14   Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
,
Roberto Elosua
13   Cardiovascular Epidemiology and Genetics Research Group, IMIM, Barcelona, Spain
15   CIBER Cardiovascular Diseases, Instituto Carlos III, Barcelona, Spain
16   School of Medicine, University of Vic-Central University of Catalonia, Barcelona, Spain
,
Pilar Delgado
17   Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Barcelona, Spain
,
Joan Martí-Fábregas
18   Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Jerzy Krupinski
2   Department of Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain
19   Centre for Bioscience, School of HealthCare Science, Manchester Metropolitan University, Manchester, England
,
Jaume Roquer
4   Neurovascular Research Group, Department of Neurology, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Jordi Jiménez-Conde
4   Neurovascular Research Group, Department of Neurology, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
,
Israel Fernández-Cadenas
1   Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
2   Department of Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain
› Author Affiliations Funding The EPIGENESIS project (Carlos III Institute—PI17/02089, Marató TV3 and Fundació MútuaTerrassa), the MAESTRO project—PI18/01338 (Carlos III Institute), the iBioStroke project (Eranet-Neuron, European research grants), the EPINEXO project—PI20/00678 (Carlos III Institute), the SEDMAN Study (Boehringer Ingelheim), the APHAS project (Pfizer/Bristol-Myers Squibb), and the European Regional Development Fund (ERDF)/Fondo Europeo de Desarrollo Regional (FEDER) and 2017SGR-1427 (AGAUR). I.F.-C is the recipient of a research contract from the Miguel Servet Program (CP12/03298) from the Carlos III Institute. J.C.-M. is supported by an AGAUR contract (Agència de Gestió d'Ajuts Universitaris i de Recerca; FI_DGR 2019, grant number 2019_FI_B 00853) co-financed by Fons Social Europeu (FSE). M.L. is supported by a PFIS contract (Contratos Predoctorales de Formación en Investigación en Salud): FI19/00309. C.G.-F is supported by a Sara Borrell contract (CD20/00043) from the Carlos III Institute and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). E.M. is supported by a Río Hortega contract (CM18/00198) from the Carlos III Institute.
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Abstract

Background Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS).

Methods We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites.

Results A total of 957 CpG sites were epigenome-wide-significant (p ≤ 10−7) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058, p = 2.35 × 10−22; logFC = 0.035, p = 3.22 × 10−22, respectively). ZFHX3 and MAP3K1 were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-corrected p-values (p < 5.22 × 10−5). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress. ZFHX3 and MAP3K1 methylation was causally associated with specific stroke-subtype risk.

Conclusion Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets.

Keywords

stroke - DNA methylation - epigenetics - epigenome-wide association studies - EWAS

* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 21 September 2021

Accepted: 12 April 2022

Article published online:
19 June 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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